Changes in vascular biochemical and biomechanical properties may lead to altered distensibility early in atherogenesis. Methods quantitating changes would facilitate the evaluation of new therapies earlier in the disease process. We examined whether ultrasound could be used to determine the severity of atherosclerosis in rabbits. Doppler ultrasound and ECG recordings were taken at the descending aortic arch and at the bifurcation of the iliac arteries of control (NZW) and Watanabe heritable hyperlipidemic (WHHL) rabbits in order to determine pulse wave transit times (tarch and tiliac, respectively). Aortic segments were excised, and direct compliance assessments were performed by determining the change in diameter of each segment following saline pressurization. Analysis of these aortic segments showed a 30-45 fold increase in aortic cholesterol (chol) in WHHL rabbits compared to NZW. Direct compliance was decreased 35% (P<0.0001), transit times were reduced 20% at both the arch (P<0.01) and at the iliac bifurcation(P<0.0001) in WHHL rabbits compared to NZW. These parameters correlated significantly with compliance measurements (tiliac,r=0.63,P=0.003; tarch,r=0.45,P=0.048). Plasma chol was inversely correlated with tililac(r=-0.85,P<0.001), tarch(r=-0.57,P=0.009), and compliance (r=-0.68,P=0.001). A positive correlation was found when HDL chol was compared with tiliac(r=0.57,P=0.01), tarch (r=0.46,P=0.05), and compliance (r=0.64,P=0.003). Aortic chol content also correlated significantly with tiliac (r=-0.79,P<0.001), tarch (r=-0.64,P=0.004), and compliance (r=-0.69,P=0.001). We conclude that Doppler ultrasound can be used to determine vascular changes in vivo that reflect ex vivo compliance. As atherosclerosis becomes more severe, compliance and pulse wave transit time significantly decrease.